Project Summary This proposal seeks to define the role of a key protein quality control protein, UBQLN2, in the age-related neurodegenerative disorders known as synucleinopathies and tauopathies, which include Parkinson?s and Alzheimer?s disease. These common disorders are characterized by the accumulation of the proteins tau and ?-synuclein, which adopt non-native conformations causing them to aggregate within brain cells. There are currently no effective disease-modifying therapies and the factors precipitating neurodegeneration remain poorly understood in these disorders. UBQLN2 is implicated in the cellular clearance of misprocessed and toxic proteins, principally via the proteasome, but its role in handling neurodegenerative disease proteins, tau and ?-synuclein, has not been explored. Rare mutations in the UBQLN2 gene can directly cause age-related neurodegenerative disease, but accumulation of normal UBQLN2 is commonly associated with many disorders, including Alzheimer?s disease, Parkinson?s disease, Huntington?s disease and frontotemporal dementia. Preliminary evidence suggests that UBQLN2 is highly effective at reducing levels of tau and ?- synuclein in cells, doing so much more robustly than the closely related protein, UBQLN1. In two aims, the studies proposed here will investigate how UBQLN2 interacts with tau and ?-synuclein to regulate their levels in disease. In the first aim, cellular models will be used to define which functional domains of UBQLN2 mediate its regulation of tau and ?-synuclein and which cellular processes (e.g. proteasome, autophagy) are responsible for the clearance of disease proteins by UBQLN2; comparisons to UBQLN1, including domain swapping between the two proteins, will help establish the basis of protein clearance. In the second aim, mouse models will be used to determine whether UBQLN2 regulates levels of tau or ?-synuclein in the brain in a manner that mitigates pathological accumulation of either protein. The proposed studies are expected to yield new insights into the role of UBQLN2 in common age-related neurodegenerative diseases that will suggest routes to therapeutic intervention.